Therapeutic compounds for pain and synthesis thereof

ABSTRACT

The invention provides compounds of Formula 1: 
     
       
         
         
             
             
         
       
     
     and stereoisomers, pharmaceutically acceptable salts and derivatives thereof; and methods of making and using such compounds. The invention includes pharmaceutical compositions containing such compounds, and the use of such compounds in methods of treating conditions, diseases, or disorders.

RELATED APPLICATIONS

This patent application claims the benefit of U.S. ProvisionalApplication Ser. No. 62/214,727, filed Sep. 4, 2015, and U.S.Provisional Application Ser. No. 62/214,734, filed Sep. 4, 2015, each ofwhich is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The invention provides new pharmaceutically active chemical compounds,which can be used for treating conditions and disorders in animals,mammals, and humans.

BACKGROUND

New chemical compounds having pharmaceutical activity can be indicatedfor the treatment of previously untreatable conditions, better treatmentof conditions than can be achieved with conventional pharmaceuticalcompounds, and treatment of conditions that were previously treatablewith conventional pharmaceutical compounds, but now are no longereffectively treatable. For example, such compounds can be useful in thecase of bacterial or viral infectious agents that have evolved to becomedrug resistant.

SUMMARY OF THE INVENTION

The invention provides a compound of Formula 1:

1-(cyclopropylmethyl)-4-(3,3,3-trifluoropropanoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridin-3-ylpivalate, or a stereoisomer, pharmaceutically acceptable salt, ormixture thereof.

In certain embodiments, Formula 1 is

(2S,3S,6R,7aR)-1-(cyclopropylmethyl)-4-(3,3,3-trifluoropropanoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridin-3-ylpivalate.

In certain embodiments, the invention includes a pharmaceuticalcomposition containing a compound of Formula 1 and/or a derivativethereof. In one embodiment, the invention includes a pharmaceuticalcomposition comprising a compound of Formula 1 and/or derivative thereofand a pharmaceutically acceptable carrier or diluent. In anotherembodiment, the invention provides a method for treating a subject (ahuman or an animal) suffering from a condition, disease, or disorder,comprising administering to the subject an effective amount of acompound of Formula 1 and/or derivative thereof. In one embodiment, thecompound is administered to effect localized delivery to the subject. Inanother embodiment, the compound is administered to effect systemicdelivery to the subject. In a further embodiment, a compound of Formula1, and/or derivative thereof is used as a medicament, or used in themanufacture of a medicament. In some embodiments, the condition ordisorder is neuropathic pain or chronic pain.

In other embodiments, the method includes making the compound ofFormula 1. In one such embodiment, the method of making the compound ofFormula 1 includes reacting a compound of Formula 2:

(2S*,3S*,3aS*,6R*,7aR*)-4-(3,3,3-trifluoropropanoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridin-3-ylpivalate with cyclopropylcarboxaldehyde in the presence of a reducingagent. In some embodiments the cyclopropylcarboxaldehyde was addedbefore the reducing agent. In certain embodiments the reducing agent issodium triacetoxyborohydride. In some embodiments the compound ofFormula 1 is chirally separated.

In some embodiments, the method can also include making the compound ofFormula 2. In an embodiment, the method of making the compound ofFormula 2 includes reacting a compound of Formula 3:

(2S*,3S*,3aS*,6R*,7aR*)-tert-butyl3-(pivaloyloxy)-4-(3,3,3-trifluoropropanoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylatewith an acid. In certain embodiments, the acid is trifluoroacetic acid.

In some embodiments, the method can also include making the compound ofFormula 3. In an embodiment, the method of making the compound ofFormula 3 includes reacting a compound of Formula 4:

(2S*,3S*,3aS*,6R*,7aR*)-tert-butyl3-hydroxy-4-(3,3,3-trifluoropropanoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylatewith dimethylaminopyridine (DMAP).

In some embodiments, the method can also include making the compound ofFormula 4. In an embodiment, the method of making the compound ofFormula 4 includes reacting a compound of Formula 5:

(2S*,3S*,3aS*,6R*,7aR*)-tert-butyl3-((tertbutyldiphenylsilyl)oxy)-4-(3,3,3trifluoropropanoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylatewith tert-butyldiphenylchlorosilane. In some embodiments the reactionfurther comprises pyridine.

In some embodiments, the method can also include making the compound ofFormula 5. In an embodiment, the method of making the compound ofFormula 5 includes reacting a compound of Formula 6.b:

(2S*,3R*,3aS*,6R*,7aR*)-tert-butyl3-((tertbutyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylatewith 3,3,3-trifluoropropanoic acid. In some embodiments, the reactionfurther comprises N—N-Diisopropylethylamine. In certain embodiments, thereaction further comprises(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) sodium triacetoxyborohydride. In someembodiments, the method includes chirally separating a compound ofFormula 7:

rac-(2S*,3R*,3a S*,6R*,7aR*)-tert-butyl3-((tertbutyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate.

In other embodiments, the method includes making the compound of Formula7. In one such embodiment, the method of making the compound of Formula7 includes reacting a compound of Formula 8:

rac-(2R,3R,6S,7aS)-tert-butyl4-benzyl-3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylatewith hydrogen. The reaction may be performed in the presence of acatalyst. In a preferred embodiment, the catalyst includes palladium.For example, the catalyst can be palladium on carbon.

In other embodiments, the method includes making the compound of Formula8. In one such embodiment, the method of making the compound of Formula8 includes reacting a compound of Formula 9:

rac-(2R,3R,6S,7aS)-4-benzyl-3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridinewith di-tert-butyl dicarbonate (Boc₂O) to add a tert-butyloxycarbonyl(Boc) protecting group. In a preferred embodiment the reaction furthercomprises triethylamine (Et₃N).

In other embodiments, the method also includes making the compound ofFormula 9. In one such embodiment, the method of making the compound ofFormula 9 includes reacting a compound of Formula 10:

(2R,3R,6S,7aS)-ethyl4-benzyl-3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylatewith iodotrimethylsilane.

In other embodiments, the method also includes making the compound ofFormula 10. In one such embodiment, the method of making the compound ofFormula 10 includes reacting a compound of Formula 11:

(2R,3S,6S,7aS)-ethyl-4-benzyl-3-hydroxyoctahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylatewith TBDPS. In a preferred embodiment the reaction further comprisesimidazole.

In other embodiments, the method also includes making the compound ofFormula 11. In one such embodiment, the method of making the compound ofFormula 11 includes reacting a compound of Formula 12:

(2R,3S,6S,7aS)-ethyl3-hydroxyoctahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylatewith benzaldehyde. In a preferred embodiment the reaction furthercomprises sodium triacetoxyborohydride (STAB).

In other embodiments, the method also includes making the compound ofFormula 12. In one such embodiment, the method of making the compound ofFormula 12 includes cyclizing a compound of Formula 12.a:

(1R,2R,4S,5S,7s)-ethyl7-(aminomethyl)-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate in asolvent. The solvent can be ethanol (EtOH).

In other embodiments, the method also includes making the compound ofFormula 12.a. In one such embodiment, the method of making the compoundof Formula 12.a includes reacting a compound of Formula 13:

(1R,2R,4S,5S,7s)-ethyl7-cyano-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate withhydrogen. The reaction may be performed in the presence of a catalyst.In one embodiment, the catalyst includes nickel. For example, thecatalyst can be Raney-nickel.

In other embodiments, the method also includes making the compound ofFormula 13. In one such embodiment, the method of making the compound ofFormula 13 includes reacting a compound of Formula 14:

(1R,2R,4S,5S,7r)-ethyl7-((methylsulfonyl)oxy)-3-oxa-9-azatricyclo[3.0.1.02,4]nonane-9-carboxylatewith potassium cyanide. In other embodiments the reaction furthercomprises 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane).

In other embodiments, the method also includes making the compound ofFormula 14. In one such embodiment, the method of making the compound ofFormula 14 includes reacting a compound of Formula 15:

(1R,2R,4S,5S,7r)-ethyl7-hydroxy-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate with mesylchloride. In a preferred embodiment the reaction further comprisestriethylamine (ET₃N).

In other embodiments, the method also includes making the compound ofFormula 15. In one such embodiment, the method of making the compound ofFormula 15 includes reacting a compound of Formula 16:

(1R,2R,4S,5S,7r)-ethyl7-(benzoyloxy)-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate witha reducing agent. The reducing agent can be sodium borohydride.

In other embodiments, the method also includes making the compound ofFormula 16. In one such embodiment, the method of making the compound ofFormula 16 includes reacting a compound of Formula 17:

(1R,2R,4S,5S,7r)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-ylbenzoate with ethyl chloroformate. In a preferred embodiment thereaction further comprises a base. The base can be potassium carbonate.

In other embodiments, the method also includes making the compound ofFormula 17. In one such embodiment, the method of making the compound ofFormula 17 includes reacting a compound of Formula 18:

(1R,2R,4S,5S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-ol) withbenzoic acid in the presence of an activating agent. The activatingagent can be diethylazodicaroxylate (DEAD) with triphenylphosphine(PPh₃) or diisopropyl azodicarboxylate (DIAD) with PPh₃.

In other embodiments, the method also includes making the compound ofFormula 18. In one such embodiment, the method of making the compound ofFormula 18 includes reacting a compound of Formula 19:

(2S)-(1R,2R,4S,5S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-yl-3-hydroxy-2-phenylpropanoatehydrobromide trihydrate (scopolamine) with a reducing agent. Thereducing agent can be sodium borohydride. In a preferred embodiment thereaction further comprises HCl in isopropyl alcohol.

In some embodiments, the compounds described herein are used in thetreatment or prevention of neuropathic pain in a subject in need. Inother embodiments the compounds described herein are useful in thetreatment or prevention of chronic pain in a subject in need.

BRIEF DESCRIPTION OF THE DRAWINGS

The preceding Summary, as well as the following Detailed Description ofthe invention, can be better understood when read in conjunction withthe appended Figures. For the purpose of illustrating the invention, theFigures demonstrate embodiments of the present invention. However, itshould be understood that the invention is not limited to the precisearrangements, examples, and instrumentalities shown.

FIG. 1 shows the results of a ^(1H)NMR (CDCl₃) analysis of the compoundof Formula 18, according to one embodiment of the invention.

FIG. 2 shows the results of a MS analysis of the compound of Formula 17,according to one embodiment of the invention.

FIGS. 3A and 3B show the results of a structural analysis of thecompound of Formula 16. FIG. 3A shows the results of a ^(1H)NMR analysisof the compound of Formula 16. FIG. 3B shows the results of a MSanalysis of the compound of Formula 16.

FIG. 4 shows the results of a ^(1H)NMR analysis of the compound ofFormula 15.

FIG. 5 shows the results of a ^(1H)NMR analysis of the compound ofFormula 14.

FIG. 6 shows the results of a ^(1H)NMR analysis of the compound ofFormula 13.

FIG. 7 shows the results of a ^(1H)NMR analysis of the compound ofFormula 12.

FIGS. 8A and 8B show the results of a structural analysis of thecompound of Formula 11. FIG. 8A shows the results of a MS analysis ofthe compound of Formula 11. FIG. 8B shows the results of a ^(1H)NMRanalysis of the compound of Formula 11.

FIGS. 9A and 9B show the results of a structural analysis of thecompound of Formula 10. FIG. 9A shows the results of a LCMS analysis ofthe compound of Formula 10. FIG. 9B shows the results of a ^(1H)NMRanalysis of the compound of Formula 10.

FIG. 10 shows the results of a LCMS analysis of the compound of Formula9.

FIGS. 11A and 11B show the results of a structural analysis of thecompound of Formula 8. FIG. 11A shows the results of a ^(1H)NMR analysisof the compound of Formula 8. FIG. 11B shows the results of a LCMSanalysis of the compound of Formula 8.

FIGS. 12A and 12B show the results of a structural analysis of thecompound of Formula 7. FIG. 12A shows the results of a LCMS analysis ofthe compound of Formula 7. FIG. 12B shows the results of a ^(1H)NMRanalysis of the compound of Formula 7.

FIG. 13 shows the results of a ^(1H)NMR analysis of the compound ofFormula 2.

DETAILED DESCRIPTION

Embodiments of the invention are discussed in detail below. Indescribing these embodiments, specific terminology is employed for thesake of clarity. However, the invention is not intended to be limited tothe specific terminology selected. A person skilled in the relevant artwill recognize that other equivalent parts can be employed and othermethods developed without Certain Definitions

The term “alkyl” refers to branched or unbranched hydrocarbon chains, infor example, hydrocarbon chains having from 1 to 12 carbon atoms in thechain. In some embodiments, an alkyl group is a C₁-C₆ alkyl group. Insome embodiments, an alkyl group is a C₁-C₄ alkyl group. Examples ofalkyl groups include methyl (Me) ethyl (Et), n-propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl,hexyl, isohexyl, and groups that in light of the ordinary skill in theart and the teachings provided herein would be considered equivalent toany one of the foregoing examples.

The term “haloalkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain and having at least one ofthe hydrogens replaced with a halogen. In some embodiments, a haloalkylgroup is a C₁-C₆ haloalkyl group. In some embodiments, a haloalkyl groupis a C₁-C₄ haloalkyl group. One exemplary substitutent is fluoro.Preferred substituted alkyl groups of the invention includetrihalogenated alkyl groups such as trifluoromethyl groups. Haloalkylincludes and is not limited to CF₃, CH₂F, —CHF₂, —CH₂C₁, —CH₂—CF₃, andthe like.

“Cycloalkyl” refers to monocyclic, non-aromatic hydrocarbon groupshaving from 3 to 7 carbon atoms. Examples of cycloalkyl groups include,for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and thelike.

The term “alkoxy” includes a straight chain or branched alkyl group witha terminal oxygen linking the alkyl group to the rest of the molecule.In some embodiments, an alkoxy group is a C₁-C₆ alkoxy group. In someembodiments, an alkoxy group is a C₁-C₄ alkoxy group. Alkoxy includesmethoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and soon.

The term “heterocycle” represents” a mono- or bi-cyclic hydrocarbon ringstructure optionally containing heteroatoms selected from O, S, and N.Heterocyclyl rings can have 2 to 10 carbon atoms in the ring.

The term “halogen” represents chlorine, fluorine, bromine, or iodine.The term “halo” represents chloro, fluoro, bromo, or iodo.

A wavy line “

” indicates the point of attachment to the rest of the molecule.

“Benzyl” and —CH₂-phenyl are used interchangeably.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, and more particularly, in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-di sulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non-toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound of the invention isadministered. A “pharmaceutically acceptable excipient” refers to asubstance that is non-toxic, biologically tolerable, and otherwisebiologically suitable for administration to a subject, such as an inertsubstance, added to a pharmacological composition or otherwise used as avehicle, carrier, or diluent to facilitate administration of a agent andthat is compatible therewith. Examples of excipients include calciumcarbonate, calcium phosphate, various sugars and types of starch,cellulose derivatives, gelatin, vegetable oils, and polyethyleneglycols.

“Subject” includes humans. The terms “human,” “patient,” and “subject”are used interchangeably herein.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

In treatment methods according to the invention, a therapeuticallyeffective amount of a pharmaceutical agent according to the invention isadministered to a subject suffering from or diagnosed as having such adisease, disorder, or condition. A “therapeutically effective amount”means an amount or dose sufficient to generally bring about the desiredtherapeutic or prophylactic benefit in patients in need of suchtreatment for the designated disease, disorder, or condition.

Effective amounts or doses of the compounds of the present invention maybe ascertained by routine methods such as modeling, dose escalationstudies or clinical trials, and by taking into consideration routinefactors, e.g., the mode or route of administration or drug delivery, thepharmacokinetics of the compound, the severity and course of thedisease, disorder, or condition, the subject's previous or ongoingtherapy, the subject's health status and response to drugs, and thejudgment of the treating physician. An example of a dose is in the rangeof from about 0.001 to about 200 mg of compound per kg of subject's bodyweight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID). Fora 70-kg human, an illustrative range for a suitable dosage amount isfrom about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.

“Compounds of the present invention,” and equivalent expressions, aremeant to embrace compounds of the Formula as described herein, whichexpression includes the pharmaceutically acceptable salts, and thesolvates, e.g., hydrates, where the context so permits. Similarly,reference to intermediates, whether or not they themselves are claimed,is meant to embrace their salts, and solvates, where the context sopermits.

As used herein, the term “isotopic variant” refers to a compound thatcontains unnatural proportions of isotopes at one or more of the atomsthat constitute such compound. For example, an “isotopic variant” of acompound can be radiolabeled, that is, contain one or morenon-radioactive or radioactive isotopes, such as for example, deuterium(²H or D), carbon-13 (¹³C), nitrogen-15 (¹⁵N), or the like. It will beunderstood that, in a compound where such isotopic substitution is made,the following atoms, where present, may vary, so that for example, anyhydrogen may be ²H/D, any carbon may be ¹³C, or any nitrogen may be ¹⁵N,and that the presence and placement of such atoms may be determinedwithin the skill of the art. Likewise, the invention may include thepreparation of isotopic variants with radioisotopes, in the instance forexample, where the resulting compounds may be used for drug and/orsubstrate tissue distribution studies. Radiolabeled compounds of theinvention can be used in diagnostic methods such as single-photonemission computed tomography (SPECT). The radioactive isotopes tritium,i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for their easeof incorporation and ready means of detection. Further, compounds may beprepared that are substituted with positron emitting isotopes, such as¹¹C, ¹⁸F, ¹⁵O and ¹³N, and would be useful in Positron EmissionTopography (PET) studies for examining substrate receptor occupancy.

All isotopic variants of the compounds of the invention, radioactive ornot, are intended to be encompassed within the scope of the invention.In one aspect, provided herein are deuterated or tritiated analogs ofcompounds described.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers.” Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers.”

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers.” When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture.”

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of it electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenyl nitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

Compounds of the invention may also exist as “rotamers,” that is,conformational isomers that occur when the rotation leading to differentconformations is hindered, resulting a rotational energy barrier to beovercome to convert from one conformational isomer to another.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof.

Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art.

As used herein, the term “localized delivery” denotes delivery of apharmaceutical or therapeutic agent to a specific, limited region of thebody.

As used herein, the term “systemic delivery” denotes delivery of apharmaceutical or therapeutic agent throughout the body, for example,through administration to the circulatory system.

As used herein, the term “mass spectrometry (MS)” denotes an analytictechnique that ionizes a chemical compound to generate charged moleculesor molecule fragments and measures their abundance as a function ofmass-to-charge (m/z) ratio (the mass spectrum). From the mass spectrum,conclusions as to the structure of the chemical compound can be drawn.

As used herein, the term “liquid chromatography-mass spectrometry(LCMS)” denotes an analytic technique that combines the physicalseparation capability of liquid chromatography with the analyticcapability of mass spectrometry. In the liquid chromatography step, thesample is introduced into a column packed with a stationary phase,separating the chemical compounds of the sample by their retention time(Rt) in the column. The chemical compound or compounds associated with aretention time interval are then directed to a mass spectrometer, toobtain a mass spectrum that allows conclusions as to the structure ofthis chemical compound or compounds to be drawn.

As used herein, the term “thin-layer chromatography (TLC)” denotes ananalytic technique that separates chemical compounds in a sample by thedifferent rates in which they are drawn up a plate coated with astationary phase material.

As used herein, the term “nuclear magnetic resonance spectroscopy (NMR)”denotes an analytic technique that measures the intensity of a resonanceresponse of a set of nuclei to a radio frequency pulse to allowinformation as to the electronic environment of the nuclei to beobtained. From this, conclusions can be drawn as to the chemicalstructure of the compound in which the nuclei reside. A nuclear magneticresonance spectroscopy technique that uses hydrogen nuclei (protons) istermed proton nuclear magnetic resonance spectroscopy (^(1H)NMR).

The term “ester” is used herein as is conventional in the field oforganic chemistry. For example, the term “ester” can denote a carbonylgroup with a bonded oxygen and alkyl or an oxygen with a bonded carbonyland alkyl.

As used herein, the term “metabolic syndrome” denotes a medical orbiological disorder of energy utilization and storage in an animal orhuman, which can be characterized by abdominal obesity, elevated bloodpressure, elevated fasting plasma glucose, high serum triglycerides,and/or low high-density cholesterol levels.

As used herein, the term “polymerase chain reaction” denotes abiomedical technique for generating many copies of a particular DNAsequence.

As used herein, the term “triturate” denotes a method of purifying amaterial in which the crude material is washed with a solvent. Thesolvent can be selected, so that the desired product is insoluble andthe impurities are soluble, in which case, the purified product is leftin solid form and the impurities are removed with the solvent.Conversely, the solvent can be selected, so that the desired product issoluble and the impurities are insoluble, in which case, the purifiedproduct is in solution and the impurities are removed as solids. Thesolvent can then be removed, for example, through evaporation, to obtainthe purified product.

As used herein, the term “Boc-protection” denotes functionalization of achemical compound with a tert-butyloxycarbonyl (Boc) group as aprotecting group. This allows the chemical compound as a whole to betreated with reagents that would otherwise undesirably attack theunprotected group. The protected group can thereafter be deprotected toyield the desired original group.

Exemplary Compounds

The present invention, provides a molecule having the structure of acompound of the structure of Formula 1:

(2S,3S,6R,7aR)-1-(cyclopropylmethyl)-4-(3,3,3-trifluoropropanoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridin-3-ylpivalate, and stereoisomers thereof. This compound can be prepared bythe reaction sequences described in the Schemes set forth in Example 1.

Pharmaceutical Compositions and Administration

The compounds of the present invention are useful as pharmaceuticalagents and can be incorporated into pharmaceutical compositionscomprising a therapeutically effective amount of a compound of theinvention, as defined herein, and a pharmaceutically acceptable carrieror diluent.

The compounds of the invention can also be used in the manufacture ofderivative compounds that are useful as pharmaceutical agents, and whichcan likewise be incorporated into pharmaceutical compositions preparedwith a therapeutically effective amount of such a derivative compoundand a pharmaceutically acceptable carrier or diluent.

The compounds of the invention, and such derivatives thereof, can beuseful in the treatment of conditions, diseases, and disorders in humansand animals. Such compounds can be formulated as pharmaceuticalcompositions and administered to a subject in need of treatment, forexample a mammal, such as a human patient, in a variety of forms adaptedto the chosen route of administration. For example compounds of theinvention may be formulated for administration, orally, nasally,intraperitoneally, or parenterally, by intravenous, intramuscular,topical, or subcutaneous routes, or by injection into tissue.

Thus, compounds of the invention may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier, or by inhalationor insufflation. They may be enclosed in hard or soft shell gelatincapsules, may be compressed into tablets, or may be incorporateddirectly with the food of the patient's diet. For oral therapeuticadministration, the compounds may be combined with one or moreexcipients and used in the form of ingestible tablets, buccal tablets,troches, capsules, elixirs, suspensions, syrups, wafers, and the like.The compounds may be combined with an inert powdered carrier and inhaledby the subject or insufflated. Such compositions and preparations shouldcontain at least 0.1% of a compound of the present invention. Thepercentage of the compound of the invention present in such compositionsand preparations may, of course, be varied and may conveniently bebetween about 2% to about 60% of the weight of a given unit dosage form.The amount of the compound in such therapeutically useful compositionsis such that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid, and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose, or aspartame, or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or for otherwise modifying the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac, or sugar, and the like. A syrup or elixirmay contain the active compound, sucrose or fructose as a sweeteningagent, methyl and propylparabens as preservatives, a dye, and flavoringsuch as cherry or orange flavor. Of course, any material used inpreparing any unit dosage form should be pharmaceutically acceptable andsubstantially non-toxic in the amounts employed. In addition, thecompounds may be incorporated into sustained-release preparations anddevices. For example, the compounds may be incorporated into timerelease capsules, time release tablets, time release pills, and timerelease polymers or nanoparticles.

The compounds may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the compoundscan be prepared in water, optionally mixed with a nontoxic surfactant.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols, triacetin, and mixtures thereof, and in oils. Under ordinaryconditions of storage and use, these preparations can contain apreservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the compounds which are adapted for the extemporaneouspreparation of sterile injectable or infusible solutions or dispersions,optionally encapsulated in liposomes. In all cases, the ultimate dosageform should be sterile, fluid, and stable under the conditions ofmanufacture and storage. The liquid carrier or vehicle can be a solventor liquid dispersion medium comprising, for example, water, ethanol, apolyol (for example, glycerol, propylene glycol, liquid polyethyleneglycols, and the like), vegetable oils, nontoxic glyceryl esters, andsuitable mixtures thereof. The proper fluidity can be maintained, forexample, by the formation of liposomes, by the maintenance of therequired particle size in the case of dispersions, or by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars, buffers, or sodium chloride. Prolongedabsorption of the injectable compositions can be brought about by theuse in the compositions of agents delaying absorption, for example,aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the compoundsin the required amount in the appropriate solvent with various of theother ingredients enumerated above, as required, preferably followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and freeze drying techniques, which yield a powder ofthe active ingredient plus any additional desired ingredient present inthe previously sterile-filtered solutions.

For topical administration, the compounds may be applied in pure form.However, it may be desirable to administer them to the skin ascompositions or formulations, in combination with a dermatologicallyacceptable carrier, which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina, and the like. Other solidcarriers include nontoxic polymeric nanoparticles or microparticles.Useful liquid carriers include water, alcohols, or glycols, orwater/alcohol/glycol blends, in which the compounds can be dissolved ordispersed at effective levels, optionally with the aid of non-toxicsurfactants. Adjuvants such as fragrances and additional antimicrobialagents can be added to optimize the properties for a given use. Theresultant liquid compositions can be applied from absorbent pads, usedto impregnate bandages and other dressings, or sprayed onto the affectedarea using pump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses, or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds to the skin are known to the art; for example, seeJacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No.4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S.Pat. No. 4,820,508), all of which are hereby incorporated by reference.

The concentration of the therapeutic compounds of the invention in suchformulations can vary widely depending on the nature of the formulationand intended route of administration. For example, the concentration ofthe compounds in a liquid composition, such as a lotion, can preferablybe from about 0.1-25% by weight, or, more preferably, from about 0.5-10%by weight. The concentration in a semi-solid or solid composition suchas a gel or a powder can preferably be about 0.1-5% by weight, or, morepreferably, about 0.5-2.5% by weight.

Effective dosages and routes of administration of agents of theinvention are conventional. The exact amount (effective dose) of theagent will vary from subject to subject, depending on, for example, thespecies, age, weight, and general or clinical condition of the subject,the severity or mechanism of any disorder being treated, the particularagent or vehicle used, the method and scheduling of administration, andthe like. A therapeutically effective dose can be determinedempirically, by conventional procedures known to those of skill in theart. See, e.g., The Pharmacological Basis of Therapeutics, Goodman andGilman, eds., Macmillan Publishing Co., New York. For example, aneffective dose can be estimated initially either in cell culture assaysor in suitable animal models. The animal model may also be used todetermine the appropriate concentration ranges and routes ofadministration. Such information can then be used to determine usefuldoses and routes for administration in humans. Methods for theextrapolation of effective dosages in mice and other animals to humansare known to the art; for example, see U.S. Pat. No. 4,938,949, which ishereby incorporated by reference. A therapeutic dose can also beselected by analogy to dosages for comparable therapeutic agents.

The particular mode of administration and the dosage regimen will beselected by the attending clinician, taking into account the particularsof the case (e.g., the subject, the disease, the disease state involved,and whether the treatment is prophylactic). Treatment may involve dailyor multi-daily doses of compound(s) over a period of a few days tomonths, or even years.

In general, however, a suitable dose will be in the range of from about0.001 to about 100 mg/kg of body weight per day, preferably from about0.01 to about 100 mg/kg of body weight per day, more preferably, fromabout 0.1 to about 50 mg/kg of body weight per day, or even morepreferred, in a range of from about 1 to about 10 mg/kg of body weightper day. For example, a suitable dose may be about 1 mg/kg, 10 mg/kg, or50 mg/kg of body weight per day.

The compounds are conveniently administered in unit dosage form; forexample, containing about 0.05 to about 10000 mg, about 0.5 to about10000 mg, about 5 to about 1000 mg, or about 50 to about 500 mg ofactive ingredient per unit dosage form.

The compounds can be administered to achieve peak plasma concentrationsof, for example, from about 0.25 to about 200 μM, about 0.5 to about 75μM, about 1 to about 50 μM, about 2 to about 30 μM, or about 5 to about25 μM. Exemplary desirable plasma concentrations include at least 0.25,0.5, 1, 5, 10, 25, 50, 75, 100 or 200 μM. For example, plasma levels maybe from about 1 to about 100 micromolar or from about 10 to about 25micromolar. This may be achieved, for example, by the intravenousinjection of a 0.05 to 5% solution of the compounds, optionally insaline, or orally administered as a bolus containing about 1 to about100 mg of the compounds. Desirable blood levels may be maintained bycontinuous or intermittent infusion.

The compounds may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, as onedose per day or as two, three, four or more sub-doses per day. Thesub-dose itself may be further divided, e.g., into a number of discreteloosely spaced administrations; such as multiple inhalations from aninsufflator.

All documents, references, and information, including, but not limitedto, journal articles, patent applications, and patents, that arementioned, cited, or referred to in this application are herebyincorporated by reference in their entirety as if each had beenindividually incorporated.

Example 1 Synthesis of a Compound of Formula I

A compound of Formula 1 was synthesized, from the compound of Formula 19(Scopolamine [51-34-3])((2S)-(1R,2R,4S,5S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-yl-3-hydroxy-2-phenylpropanoatehydrobromide trihydrate) by the steps described below in Schemes 1through 18.

A first step is illustrated in Scheme 1.

Inside a 10 liter four necked round bottom flask, sodium borohydride(172 g, 4558 mmol) was added portion wise over about 2 hours to amechanically stirred suspension of a compound of Formula 19 (333 g, 760mmol) in 3 liters of absolute ethanol in an ice bath. During this time,gas formation occurred and the suspension was stirred while being warmedto ambient temperature overnight. While being heated, at approximately10° C., sudden additional gas formation and foaming occurred.

The milky suspension was then concentrated to about half of its originalvolume (i.e. from about 3 L to 1.5 L) with additional precipitateobserved, which yielded the batch. 5 M HCl in isopropyl alcohol (IPA)(5318 mmol, 1.064 L) was then diluted with 2 L of technical diethylether (Et₂O). The obtained hydrochloric acid (HCl) solution was thenadded drop wise to the ice-chilled batch, while being stirred. The whitesuspension was allowed to be mechanically stirred overnight to allow forfull hydrolysis of the borate salts.

The reaction mixture was filtered and the resulting solid was rinsedtwice with 500 mL portions of Et₂O. The dried solid (which containedsome Et₂O) was dissolved in a minimum amount of 10% aqueous potassiumcarbonate (K₂CO₃) solution (˜1.5 L) until just a clear solution wasobtained. 200 mL of brine and ˜50 g solid NaCl was added to thesolution. The aqueous phase was then thoroughly extracted withchloroform/methanol (MeOH)/[7N NH₃ in MeOH] (85:14:1). This procedurewas performed 5 times with 1.0 L portions of this solvent mixture each.

The combined organic extracts were dried (sodium sulphate (Na₂SO₄)),filtered and the solvent was removed under reduced pressure to give102.2 g (659 mmol) of a compound of Formula 18((1R,2R,4S,5S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-ol) as aslightly tan oil at 87% yield. ^(1H)NMR (CDCl₃) (FIG. 1) showedstructural agreement with the compound of Formula 18 with minor amountsof impurities. ^(1H)NMR (400 MHz, Chloroform-d) δ 4.03-4.00 (m, 1H),3.67 (s, 2H), 3.20-3.18 (m, 2H), 2.52 (s, 3H), 2.14-2.08 (m, 2H),1.69-1.37 (m, 3H).

The next step proceeded as illustrated by Scheme 2.

To a solution of the compound of Formula 18 (102.2 g, 659 mmol), benzoicacid (BzOH) (97 g, 790 mmol) and triphenylphosphine (PPh₃) (207 g, 790mmol) in 1000 mL of dry tetrahydrofuran (THF) a solution of diisopropylazodicaboxylate (DIAD) (160 g, 790 mmol, 154 mL) in 100 mL of dry THFwas added drop wise over a period of 4 hours. During the addition thesolution was kept between −35 and −25° C. using acetone/dry ice. Theclear, colorless solution was then removed from the ice bath and stirredat room temperature overnight.

Samples were taken and analyzed, and the analysis showed the reactionwent to completion. The reaction mixture was concentrated, dissolved in1 L of ethyl acetate (EtOAc), extracted with 1 L of saturated sodiumbicarbonate (NaHCO₃), and subsequently with aqueous 2 M HCl (1×1 L,2×0.5 L). The combined acidic aqueous fractions were washed once morewith 1 L of EtOAc. Approximately 400 g of potassium carbonate (K₂CO₃)was added portion wise to the acidic aqueous layer, while being stirred,until no more gas formation was observed. The pH of the resultingsolution was slightly basic and slightly turbid and yellow.

The aqueous phase was then extracted with a dichloromethane (DCM)/MeOH9:1 (3×, 1 L each) solution and the combined organic fractions weredried with sodium sulfate (Na₂SO₄), filtered and concentrated to afford118.3 g (447 mmol) of a compound of Formula 17((1R,2R,4S,5S,7r)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-ylbenzoate), which was then confirmed by MS (FIG. 2) to have 98% purity at67.9% yield. ^(1H)NMR (400 MHz, Chloroform-δ 8.07-7.93 (m, 2H),7.59-7.48 (m, 1H), 7.44-7.40 (m, 2H), 5.39-5.30 (m, 1H), 3.63 (s, 2H),3.42-3.25 (m, 2H), 2.57 (s, 3H), 2.10-2.04 (m, 2H), 1.92-1.86 (m, 2H).

The next step proceeded as illustrated in Scheme 3.

To a solution of the compound of Formula 17 (201.9 g, 779 mmol) inchloroform (350 mL) under a nitrogen atmosphere (not a stream), K₂CO₃(452 g, 3270 mmol) and ethyl chloroformate (279 g, 2569 mmol, 247 mL)were added to form a light yellow suspension which was then stirredunder reflux overnight.

A sample was then taken and analyzed to show that the reaction hadreached a 74% conversion to the product, a compound of Formula 16(1R,2R,4S,5S,7r)-ethyl7-(benzoyloxy)-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate). Themixture was further stirred at reflux temperature for another 24 hours.

Another sample was then taken and analyzed which showed that thereaction had reached a 75% conversion to product. In order to drive thereaction toward completion, additional K₂CO₃ (53.8 g, 389 mmol) andethyl chloroformate (85 g, 779 mmol, 74.8 mL) were added to the reactionsolution and the mixture was stirred at reflux temperature overnight.

After being stirred and refluxed overnight, another sample was takenwhich was analyzed to show that the reaction had reached 81% conversionto the compound of Formula 16.

The reaction mixture was then diluted with 500 mL of DCM and the organiclayer was washed with 750 mL of a half saturated aqueous NaHCO₃solution, 750 mL of 0.4 M aqueous HCl, and 750 mL of brine. The mixturenext dried over Na₂SO₄, then filtered and concentrated under reducedpressure which then afforded a yellow oil. 300 mL of Heptane was addedand the mixture was vigorously stirred overnight.

A white suspension had formed which contained big white lumps which werecrushed with a spatula. The suspension was filtered over a glass filter,rinsed with approximately 250 mL of heptane and approximately 200 mL ofpentane. The suspension was then dried using a vacuum oven for 3 hoursyielding the compound of Formula 16 as a white solid (219.6 g, 692 mmol,89% yield). LCMS of the product showed a percent yield greater than 95%,with a mass and structure agreement with the desired product as shown inthe MS (FIG. 3B) and ^(1H)NMR (FIG. 3A)). ^(1H)NMR (400 MHz,Chloroform-d) δ 8.01-7.97 (m, 2H), 7.61-7.53 (m, 1H), 7.48-7.42 (m, 2H),5.48-5.39 (m, 1H), 4.58 (m, 1H), 4.48 (m, 1H), 4.16 (q, J=7.1 Hz, 2H),3.56-3.53 (m, 2H), 2.34-2.21 (m, 2H), 1.98-1.86 (m, 2H), 1.27 (t, J=7.1Hz, 3H).

The next step proceeded as illustrated in Scheme 4.

In a 6 L three necked flask, sodium borohydride (157 g, 4152 mmol) wasadded to a suspension of the compound of Formula 16 (219.6 g, 692 mmol)in 1.5 L of absolute ethanol at room temperature. The reaction wasexothermic, and had an internal temperature greater than 60° C. over aperiod of approximately 4 hours, during the reaction extreme gas/foamformation was observed. The suspension was magnetically stirred at 50°C. overnight.

A sample was then taken and analyzed by TLC to show that the reactionhad gone to completion. The resulting product was a white solid whichstopped the magnetic stirrer during the night. The mixture wasconcentrated under reduced pressure and the white solid residue waspartitioned between 1 L of chloroform and 3.5 L of half-saturatedaqueous NaHCO₃ solution. The layers were next separated and the aqueouslayer was extracted with additional chloroform (2×, 1 L each). Thecombined organic layers were washed with 1 L of brine, dried overNa₂SO₄, and filtered and concentrated under reduced pressure to affordapproximately 220 g of the product as a white solid which was stirred in0.6 L of heptane overnight with a magnetic stirrer.

The mixture was then filtered off, the product had formed spheres whichwere crushed and had 500 mL of heptane added to them. The mixture wasstirred vigorously overnight with a magnetic stirrer.

After stirring the mixture overnight, the off-white suspension stillcontained spheres which then were crushed with a spatula. The suspensionwas filtered and the residue was rinsed with approximately 300 mLheptane and dried by vacuum which yielded approximately 148 g of theproduct.

A sample was taken and analysed by ^(1H)NMR to show the structure was inagreement with the compound of Formula 15 (1R,2R,4S,5S,7r)-ethyl7-hydroxy-3-oxa-9-azatricyclo [3.3.1.02,4]nonane-9-carboxylate), (FIG.4).

The residue was then stirred in approximately 300 mL of Et₂O for 1 hour.The white suspension was filtered; and the residue was rinsed again withapproximately 300 mL of Et₂O and then dried by vacuum (under N2-flow) toyield the compound of Formula 15 (122 g, 572 mmol, 82% yield). ^(1H)NMR(400 MHz, Chloroform-d) δ 4.50 (m, 1H), 4.41 (m, 1H), 4.23-4.09 (m, 3H),3.42-3.39 (m, 2H), 2.15-2.08 (m, 2H), 1.73-1.62 (m, 2H), 1.44 (d, J=5.9Hz, 1H), 1.26 (t, J=7.1 Hz, 3H).

The next step proceeded as illustrated in Scheme 5.

Triethylamine (22.78 g, 225 mmol, 31.4 mL) and mesyl-Cl (23.64 g, 206mmol, 16.08 mL) was added drop wise to a solution of the compound ofFormula 15 (40 g, 188 mmol) in DCM (500 mL) at 0° C. Once the additionwas complete, the ice bath was removed and the slightly milky suspensionwas stirred while warming to room temperature.

After 1 hour a sample was taken and analyzed by TLC which showed fullconversion had occurred. The reaction mixture was then washed twice with500 mL of water. The DCM layer appeared milky and was dried over Na₂SO₄(which made the layer clearer), and then filtered and concentrated underreduced pressure to afford a thick oil. The oil was stripped twice withtoluene to afford 54.2 g of a light tan solid which contained 21 w %toluene.

The solid was further dried under vacuum at 50° C. until the weightremained constant at 43.2 g (148 mmol; 78.9% yield) yielding a compoundof Formula 14 ((1R,2R,4S,5S,7r)-ethyl7-((methylsulfonyl)oxy)-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate).A sample was taken and the structure was confirmed by ^(1H)NMR (FIG. 5).^(1H)NMR (400 MHz, Chloroform-d) δ 5.11-5.02 (m, 1H), 4.54-4.53 (m, 1H),4.44-4.43 (m, 1H), 4.13 (q, J=7.1 Hz, 2H), 3.47-3.45 (m, 2H), 3.00 (s,3H), 2.28-2.23 (m, 2H), 2.00-1.90 (m, 2H), 1.25 (t, J=7.1 Hz, 3H).

The next step proceeded as illustrated in Scheme 6.

Potassium cyanide (12.14 g, 186 mmol) and 18-crown-6(1,4,7,10,13,16-hexaoxacyclooctadecane) (0.493 g, 1.864 mmol) were addedto a solution of the compound of Formula 14 (19.89 g, 62.1 mmol, 91%) in300 mL of dry Dimethyl sulfoxide to form a pale yellow solution whichwas stirred at 65° C. for two and a half days, or approximately 65hours, to yield a light brown solution.

A sample was taken and analyzed by TLC (heptane/DME 1:1, molybdatestaining required), which showed a clean conversion to the desiredproduct (no exo-epimeric sideproduct observed). However, at this time,it was found that the reaction had not run to completion as startingmaterial was also observed. The stirring was continued for a total of118 hours, after which the brown solution was allowed to cool to roomtemperature, and combined with an additional batch before beingpartitioned between 2 L of EtOAc and 2 L of water.

The layers were separated and the organic layer was washed twice with 1L of brine, dried over Na₂SO₄, and filtered and concentrated underreduced pressure to afford the crude product, a compound of Formula 13((1R,2R,4S,5S,7s)-ethyl7-cyano-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate). Theproduct was purified by gravity column chromatography (750 g silica,heptane/[5->50% EtOAc]) to afford 15.1 g of a white solid, or a compoundof Formula 13. A sample was taken and analyzed by ^(1H)NMR (FIG. 6)which demonstrated the product was in agreement with the structure ofFormula 13, although the product did contain 10 w % of theexo-sideproduct (which was not problematic for the follow-up reactions)and 7.5 w % of heptane. The combined yield from all experiments was 7.55g, or 45% yield, after correction for solvent and side product content.^(1H)NMR (400 MHz, Chloroform-d) δ 4.53-4.52 (m, 1H), 4.43-4.41 (m, 1H),4.12 (q, J=7.1 Hz, 2H), 3.70-3.68 (m, 2H), 2.93-2.89 (m, 1H), 2.22-2.12(m, 2H), 2.04-1.98 (m, 2H), 1.24 (t, J=7.1 Hz, 3H).

The next step proceeded as illustrated in Scheme 7.

A 50% slurry of Raney-nickel in water was added to a solution of thecompound of Formula 13 (18.20 g, 82 mmol) in 350 mL of MeOH/200 mL ofammonia (7N in MeOH). The solution was kept under a nitrogen atmosphereand the Raney-nickel slurry was added until a dark black suspension wasobtained while being stirred vigorously.

The reaction vessel was evacuated and refilled with H₂ balloons, whichwas repeated twice, and then stirred at 45° C. under a H₂ atmospherecreated by the balloons. After 3 hours, a sample was taken and analyzedby TLC using heptane/dimethoxyethane (DME) 1:1, which demonstrated thereaction was complete. The reaction mixture was filtered over a shortpad of celite which was pre-rinsed with MeOH. The residue was alsorinsed with additional MeOH.

The filtrate was then concentrated under reduced pressure to give alight yellow oil. This crude product consisted mainly of the open aminesof a compound of Formula 12.a (1R,2R,4S,5S,7s)-ethyl7-(aminomethyl)-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate andto a lesser extent the (desired) cyclized amine a compound of Formula 12(rac-(2R,3S,6S,7aS)-ethyl3-hydroxyoctahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate).

To drive cyclization of the main endo-isomer to completion, theintermediate was dissolved in 500 mL of absolute ethanol, which createda light yellow solution, which was then stirred and refluxed overnight.

A sample was taken, concentrated under reduced pressure, dissolved inCDCl₃, and analyzed by ^(1H)NMR (FIG. 7) which showed the intermediate,open endo-isomer, had cyclized. It was further shown that approximately9% of the product was open exo-amine, and some solvent remained.^(1H)NMR (400 MHz, Chloroform-δ 4.46-4.01 (m, 5H), 3.50-3.44 (m, 1H),3.16-3.11 (m, 1H), 3.96-2.93 (m, 1H), 2.10-1.66 (m, 5H), 1.47 (d, J=13.3Hz, 1H), 1.26 (t, J=7.1 Hz, 3H).

The main batch, a yellow solution, was concentrated under reducedpressure and the residue was redissolved in 500 mL of CHCl₃ and driedover Na₂SO₄. The solution was filtered and concentrated to give 21.7 gof a compound of Formula 12 as a thick yellow oil which containedsolvent and the open exo-amine which was used in the next step.

The next step proceeded as illustrated in Scheme 8.

Benzaldehyde (22.74 g, 214 mmol, 21.72 mL) was added to a solution ofthe compound of Formula 12 (37.3 g, 165 mmol) in 1000 mL ofdichloromethane. After 15 minutes STAB (55.9 g, 264 mmol) was added. Thesuspension was then stirred at room temperature overnight.

The reaction mixture was washed with 1 L of water and 1 L NaHCO₃. Theorganic layer was dried with Na₂SO4₂ and concentrated to dryness toafford 55 g of the reacted product, which was next purified by gravitycolumn chromatography (600 g, Hep/5-60% ETOAc) affording: 2.2 g ofexo-Bn2N-adduct; and 35.3 g of a compound of Formula 11(rac-(2R,3S,6S,7aS)-ethyl3-hydroxyoctahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate)as analyzed and confirmed by ^(1H)NMR (FIG. 8B) and MS (FIG. 8A).^(1H)NMR (400 MHz, Chloroform-d) δ 7.35-7.30 (m, 4H), 7.26-7.22 (m, 2H),4.41-4.02 (m, 5H), 3.83-3.78 (m, 1H), 3.66 (d, J=13.3 Hz, 1H), 3.30-3.26(m, 1H), 3.11-3.06 (m, 1H), 2.35-2.31 (m, 1H), 2.07-1.88 (m, 3H),1.77-1.65 (m, 2H), 1.44 (d, J=13.9 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H).

The next step proceeded as illustrated in Scheme 9.

Imidazole (15.19 g, 223 mmol) and tert-butyldiphenylchlorosilane (30.7g, 112 mmol, 28.7 mL) were added to a solution of the compound ofFormula 11 (35.3 g, 112 mmol) in 100 mL of dry N,N-dimethylformamide toform a pale yellow solution which was stirred at room temperatureovernight.

After the stirring was complete a sample was taken and analyzed by LCMSwhich showed the reaction was complete.

The solution was then concentrated under reduced pressure to yield anoily residue which was diluted with 750 mL of DCM and washed with 750 mLof 1:1 saturated aqueous NaHCO₃ solution and water. Next the solutionwas washed with 750 mL of brine. The organic layer was dried overNa₂SO₄, filtered, and concentrated to afford approximately 65 g of thereacted product as confirmed by TLC.

The reacted product was purified by gravity column chromatography(approximately 600 g, Hep/5-15% EtOAc) which afforded 59.5 g, or a 90%yield, of a compound of Formula 10 (rac-(2R,3R,6S,7aS)-ethyl4-benzyl-3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate)as a very thick colorless oil. A sample was taken and analyzed by^(1H)NMR (FIG. 9B) and LCMS (FIG. 9A), which showed the product was inagreement with the structure of Formula 10 and contained 6 w/w %heptane. ^(1H)NMR (400 MHz, Chloroform-δ 7.72-7.66 (m, 4H), 7.47-7.36(m, 6H), 7.26-7.16 (m, 3H), 7.12-7.09 (m, 2H), 4.62-4.48 (m, 1H), 4.26(s, 1H), 4.22-4.03 (m, 3H), 3.40-3.29 (m, 2H), 2.89-2.78 (m, 2H),1.92-1.76 (m, 4H), 1.62-1.52 (m, 1H), 1.31-1.23 (m, 3H), 1.17-1.11 (m,1H), 1.02 (s, 9H).

The next step proceeded as illustrated in Scheme 10.

Iodotrimethylsilane (75.0 g, 375 mmol, 51 ml) was added to a solution ofthe compound of Formula 10 (73.9 g, 124 mmol, 93%) in 1.2 L of drytoluene to create a yellow reaction mixture which was stirred at 85° C.overnight.

A sample taken then taken and analyzed by TLC, which showed the reactionhad gone to completion. The resulting reaction mixture was a darksolution, and was allowed to cool to room temperature (suspension) andquenched with 250 mL of MeOH. The mixture was next concentrated toapproximately 250 mL. After which 750 mL of DCM was added and themixture was washed with 750 mL of 1:1 saturated aqueous NaHCO₃solution/H₂O. The organic layer was then washed with 750 mL of brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure toafford approximately 72 g, or a 92% yield, of a compound of Formula 9(rac-(2R,3R,6S,7aS)-4-benzyl-3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo [3,2-b]pyridine) as a dark yellow/orangeoil. A sample was taken and analyzed by LCMS (FIG. 10) which showed thecorrect mass, and that the product had a purity of about 80%, with thepeak at 0.448 being toluene. ^(1H)NMR (400 MHz, Chloroform-d) δ7.69-7.63 (m, 4H), 7.47-7.37 (m, 6H), 7.26-7.12 (m, 5H), 4.36 (s, 1H),3.73-3.70 (m, 1H), 3.39 (d, J=13.7 Hz, 1H), 3.26 (d, J=7.6 Hz, 1H), 3.06(s, 1H), 2.90 (d, J=13.7 Hz, 1H), 2.79-2.74 (m, 1H), 2.41 (bs, 1H),1.90-1.80 (m, 4H), 1.67-1.64 (m, 1H), 1.11-0.99 (m, 10H).

The next step proceeded as illustrated in Scheme 11.

Et₃N (48.3 g, 477 mmol, 0.067 L) and di-tert-butyl dicarbonate (Boc₂O)(39.1 g, 179 mmol) was added to a solution of the compound of Formula 9(72 g, 119 mmol, 80%) in 1 L of dichloromethane to form a light yellowsolution which was stirred at room temperature over weekend.

A sample taken and analyzed by TLC which showed the reaction wascomplete. The solution was diluted with 250 mL of DCM and washed with 1L of saturated aqueous NaHCO₃ solution and 1 L of brine. The organiclayer was then dried over Na₂SO₄, filtered, and concentrated to affordapproximately 80 g of the crude product.

Purification by gravity column chromatography (800 g, heptane/[EtOAc1->10%]) afforded 68.4 g, or a 94% yield, of a compound of the Formula 8(rac-(2R,3R,6S,7aS)-tert-butyl4-benzyl-3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate)as a colorless glass.

A sample was taken and analyzed by ^(1H)NMR (FIG. 11A) and LCMS (FIG.11B) which showed agreement between the product and the structure ofFormula 8, and further showing that the product contained 4 w/w %heptane. ^(1H)NMR (400 MHz, Chloroform-δ 7.73-7.65 (m, 4H), 7.47-7.35(m, 6H), 7.24-7.10 (m, 5H), 4.53-4.40 (m, 1H), 4.24 (d, J=3.8 Hz, 1H),4.10-3.92 (m, 1H), 3.44-3.32 (m, 2H), 2.87 (d, J=13.6 Hz, 1H), 2.33-2.77(m, 1H), 1.93-1.72 (m, 4H), 1.65-1.54 (m, 1H), 1.50-1.47 (m, 9H),1.10-1.02 (m, 10H).

The next step proceeded as illustrated in Scheme 12.

Under a nitrogen flow, Palladium, 10% on activated carbon (7 g, 125mmol) was added to a solution of the compound of Formula 8 (72.9 g, 125mmol) in 600 mL of acetic acid. The vessel was closed and the resultingmixture was stirred at 50° C. for 2 hours under a hydrogen atmospherecreated by a balloon.

The mixture was then stirred at 50° C. overnight. The black suspensionwas filtered over EtOH rinsed celite and the filtrate was concentratedunder reduced pressure. The residue was stripped twice with 0.5 L oftoluene, after which it was dissolved in 1 L of diethyl ether.

The organic layer was then washed with 1 L of 10% (w/v) aqueous K₂CO₃solution, 1 L of brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure before being stripped again with pentane toafford 58.5 g of a thick tan syrup, a compound of Formula 7(rac-(2R,3S,6S,7aS)-tert-butyl3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate).

A sample was taken and analyzed by ^(1H)NMR (FIG. 12B) and LCMS (FIG.12A) which showed the product was in agreement with structure of Formula7 and contained 5.1 weight % of toluene and 1.3 weight % of n-pentane.^(1H)NMR (400 MHz, Chloroform-d) δ 7.68-7.63 (m, 4H), 7.45-7.35 (m, 6H),4.40-4.25 (m, 1H), 4.13-3.93 (m, 2H), 3.41-3.36 (m, 1H), 2.97-2.92 (m,1H), 2.62 (d, J=11.5 Hz, 1H), 1.96-1.78 (m, 2H), 1.67 (s, 1H), 1.64-1.56(m, 1H), 1.49-1.47 (m, 9H), 1.16-1.13 (m, 1H), 1.05-1.04 (m, 9H).

The compound of Formula 7 was separated into its respective enantiomersvia supercritical fluid chromatography (SFC) on a Welkho-1 column with90/10 scCO₂/iPrOH+0.2% isopropylamine eluent as as illustrated in Scheme13.

The next step proceeded as illustrated in Scheme 14.

3,3,3-trifluoropropanoic acid (3.629 mL, 41.1 mmol, 1.5 eq) wasdissolved in DCM (120 mL) and dry DMF (10 mL). DIPEA (7.16 mL, 41.1mmol, 1.5 eq) and HATU(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidhexafluorophosphate) (15.63 g, 41.1 mmol, 1.5 eq) were added andthe mixture was stirred at room temperature for 1.5 hours. This resultedin the formation of a clear red-brown solution.

To that solution, a solution of the compound of Formula 6.b (13.5 g,27.4 mmol) in DCM (100 mL) was added and the solution was stirred for atroom temperature for 4 hours.

The reaction mixture was diluted with DCM (250 mL), washed with aqueous1 M KHSO₄ (400 mL), saturated aqueous NaHCO₃ (400 mL), water (400 mL),brine (250 mL), dried over Na₂SO₄ and concentrated in vacuo to afford22.74 g (>100%) a compound of Formula 5((2S*,3S*,3aS*,6R*,7aR*)-tert-butyl3-((tertbutyldiphenylsilyl)oxy)-4-(3,3,3trifluoropropanoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate)as a brown oil.

The next step proceeded as illustrated in Scheme 15.

The compound of Formula 5 (max 27.4 mmol) was dissolved in dry THF (115mL).

A solution of tetrabutylammonium fluoride in THF (1 M, 82 mL, 82 mmol)was added and the reaction mixture was stirred at 50° C. overnight. LCMSanalysis revealed complete conversion to desired material.

The solution was concentrated in vacuo and co-evaporated twice with 50%EtOAc/heptane (2×, each 100 mL) to afford 38.66 g of crude material as abrown oil. The material was dissolved in 25% EtOAc/Et₂O (800 mL) andwashed with water (2×, each 600 mL). The aqueous layers were combinedand extracted with 25% EtOAc/Et₂O (400 mL). The organic layers werecombined, washed with brine (400 mL), dried over Na₂SO₄ and concentratedin vacuo to afford 15.14 g of material as a brown oil.

Purification by gravitation column chromatography (gradient 50%EtOAc/heptane to 100% EtOAc) yielded 5.85 g of a compound of Formula 4((2S*,3S*,3aS*,6R*,7aR*)-tert-butyl3-hydroxy-4-(3,3,3-trifluoropropanoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate)(58% over 2 steps) as a white foam.

The next step proceeded as illustrated in Scheme 16,

The compound of Formula 4 (5.85 g, 16 mmol) was dissolved in pyridine(50 mL), followed by the addition of DMAP (dimethylaminopyridine) (1.96g, 16.06 mmol) and pivaloyl chloride (3.95 mL, 32.1 mmol).

The reaction mixture was stirred overnight at 60° C. LCMS analysisrevealed complete conversion to desired material. The reaction mixturewas allowed to cool to room temperature (a light brown suspensionformed) and concentrated in vacuo.

The residue was diluted with EtOAc (250 mL) and washed with aqueous 0.5M KHSO₄ (200 mL) and saturated aqueous NaHCO₃ (250 mL). Each time theaqueous layer was extracted with additional EtOAc (50 mL).

The combined organic layers were washed with brine (200 mL), dried withsodium sulfate, filtered and evaporated to dryness to yield 6.8 g ofcrude material. Purification by flash column chromatography(EtOAc/heptane gradient) afforded 5.49 g (76%) of a compound of Formula3 ((2S*,3S*,3aS*,6R*,7aR*)-tert-butyl3-(pivaloyloxy)-4-(3,3,3-trifluoropropanoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate)as a white foam. LCMS analysis: purity >95%. found 449.3 [M+H]+& 393.2(M−(C4H8)+H]+).

The next step proceeded as illustrated in Scheme 17.

The compound of Formula 3 (1 g, 2.23 mmol) was dissolved in DCM (20 mL).

TFA (trifluoroacetic acid) (8.54 mL, 111 mmol) was added and the mixturewas stirred at room temperature for 1 h. LCMS analysis revealed completeconversion to desired material.

The reaction mixture was concentrated in vacuo and co-evaporated withtoluene (2×, each 20 mL). The residue was dissolved in chloroform (40mL) and washed with aqueous saturated Na₂CO₃ solution (40 mL). Theaqueous phase was extracted with chloroform (3×, each 20 mL).

The organic layers were combined, washed with brine (70 mL), dried(Na₂SO₄), filtered and evaporated under reduced pressure to afford 769.9mg (99%) of a compound of Formula 2((2S*,3S*,3aS*,6R*,7aR*)-4-(3,3,3-trifluoropropanoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridin-3-ylpivalate) as an off-white solid. The structure was confirmed by ^(1H)NMRas shown in FIG. 13.

The next step proceeded as illustrated in Scheme 18,

To the compound of Formula 2 (199.8 mg; 0.574 mmol) in dichloromethane(2 mL), cyclopropylcarboxaldehyde (55.7 uL; 0.523 mmol) was added, andthe reaction mixture was stirred for 2 hours at room temperature. Nextsodium triacetoxyborohydride (200.7 mg; 0.947 mmol) was added to thereaction mixture, and the reaction mixture was stirred at roomtemperature overnight. The reaction mixtures were evaporated to drynessunder reduced pressure. Purification by prep LCMS followed byevaporation of the solvents under reduced pressure (Genevac) afforded acompound of Formula 1((2S,3S,6R,7aR)-1-(cyclopropylmethyl)-4-(3,3,3-trifluoropropanoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridin-3-ylpivalate). (MH+=403.1).

An overview of these synthetic steps to transform the starting reactantinto a compound of Formula 1 is provided in Scheme 19, below.

Example 2 In Vivo Activity of the Compound of Formula 1

Table 7 summarizes the activity of Formula 1 in mice models ofneuropathic pain following repeated daily administration using differentroutes of administration.

TABLE 7 Summary of the activity of Formula 1 in animal models forneuropathic pain in mice. Dose of Level of activity Duration of Peak ofmaximum Doses Tested (% of maximum activity at activity activity TIModel Route (mg/kg) effect- baseline) maximum effect (T) (mg/kg)Gabapentin CCI IP 150  66% 4-6 H 2-3 H 150 SC 150  64% 4-6 H 2-3 H 150SC 150 >100%  4-6 H 2-3 H 150 Gabapentin Taxol SC 150 100% 4 H 2-4 H 150Formula 1 Taxol SC 1, 3, 10 100% 3 day 1 H-3 days 1 Gabapentin Taxol PO150 100% 4 H 2-4 H 150 Formula 1 Taxol PO  30 100% 3 days 1-24 H <30

The embodiments illustrated and discussed in this specification areintended only to teach those skilled in the art the best way known tothe inventors to make and use the invention. Nothing in thisspecification should be considered as limiting the scope of the presentinvention. All examples presented are representative and non-limiting.The above-described embodiments of the invention may be modified orvaried, without departing from the invention, as appreciated by thoseskilled in the art in light of the above teachings. It is therefore tobe understood that, within the scope of the claims and theirequivalents, the invention may be practiced otherwise than asspecifically described.

It should be understood that although the compounds of Formulas 1-18 maybe drawn with specific chirality for the sake of simplicity, one skilledin the art would recognize how to create and separate these variousisomers. Accordingly, all isomers of the compounds of Formulas 1-18 maybe understood to be within the scope of the present application.

1. A compound of Formula 1:

or a stereoisomer, pharmaceutically acceptable salt, or mixture thereof.2. The compound of claim 1, wherein Formula 1 is:

or a stereoisomer, pharmaceutically acceptable salt, or mixture thereof.3. A pharmaceutical composition comprising a compound of claim 2, and apharmaceutically acceptable carrier or diluent.
 4. A method for treatinga subject (a human or an animal) suffering from a condition, disease, ordisorder, comprising administering to the subject an effective amount ofthe compound of claim
 2. 5. The method of claim 4, wherein the compoundis administered to effect localized delivery to the subject.
 6. Themethod of claim 4, wherein the compound is administered to effectsystemic delivery to the subject.
 7. The method of claim 4, wherein thecondition or disorder is neuropathic pain or chronic pain.
 8. A methodof making a compound of Formula 1:

comprising reacting a compound of Formula 2:

with cyclopropylcarboxaldehyde in the presence of a reducing agent. 9.The method of claim 8, wherein the cyclopropylcarboxaldehyde was addedbefore the reducing agent.
 10. The method of claim 8, wherein thereducing agent is sodium triacetoxyborohydride.
 11. The method of claim8, wherein the compound of Formula 1 is chirally separated.
 12. Themethod of claim 8, further comprising making the compound of Formula 2by reacting a compound of Formula 3:

with an acid.
 13. The method of claim 12, wherein the acid istrifluoroacetic acid.
 14. The method of claim 12, further comprising:making the compound of Formula 3 by reacting a compound of Formula 4:

with dimethylaminopyridine (DMAP); making the compound of Formula 4 byreacting a compound of Formula 5:

with tert-butyldiphenylchlorosilane; making the compound of Formula 5 byreacting a compound of Formula 6.b:

with 3,3,3-trifluoropropanoic acid; making the compound of Formula 6.bby chirally separating a compound of Formula 7:

making the compound of Formula 7 by reacting a compound of Formula 8:

with hydrogen in the presence of a catalyst; making the compound ofFormula 8 by reacting a compound of Formula 9:

with Boc₂O; making the compound of Formula 9 by reacting a compound ofFormula 10:

with iodotrimethylsilane; making the compound of Formula 10 by reactinga compound of Formula 11:

with tert-butyldiphenylchlorosilane; making the compound of Formula 11by reacting compounds of Formula 12:

and Formula 12.a:

with benzaldehyde in a solvent; making the compound of Formula 12 andFormula 12.a by reacting a compound of Formula 13:

with hydrogen in the presence of a catalyst; making the compound ofFormula 13 by reacting a compound of Formula 14:

with potassium cyanide; making the compound of Formula 14 by reacting acompound of Formula 15:

with mesyl chloride; making the compound of Formula 15 by reacting acompound of Formula 16:

with a reducing agent; making the compound of Formula 16 by reacting acompound of Formula 17:

with ethyl chloroformate; making the compound of Formula 17 by reactinga compound of Formula 18:

with benzoic acid in the presence of an activating agent; and making thecompound of Formula 18 by reacting a compound of Formula 19:

with a reducing agent.
 15. (canceled)
 16. The method of claim 14,wherein the step of making of the compound of Formula 4 furthercomprises pyridine; the step of making of the compound of Formula 5further comprises N—N-Diisopropylethylamine; the catalyst in the step ofmaking the compound of Formula 7 comprises palladium; the step of makingof the compound of Formula 8 further comprises triethylamine (Et₃N); thestep of method of making a compound of Formula 9 takes place at atemperature above 60° C.; the step of making a compound of Formula 10further comprises imidazole; the step of making a compound of Formula 11further comprises sodium triacetoxyborohydride and the solvent isethanol; and the catalyst in the step of making a compound of Formula12.a is Raney-nickel.
 17. (canceled)
 18. (canceled)
 19. The method ofclaim 14, wherein the making of the compound of Formula 5 furthercomprises(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) sodium triacetoxyborohydride. 20-22.(canceled)
 23. The method of claim 14, wherein the catalyst in the stepof making the compound of Formula 7 is palladium on carbon. 24-36.(canceled)
 37. The method of claim 14, wherein the step of making acompound of Formula 13 further comprises 18-crown-6; the step of makinga compound of Formula 14 further comprises triethylamine (Et₃N); thereducing agent in the step of making a compound of Formula 15 is sodiumborohydride; the step of making a compound of Formula 16 furthercomprises a base; the activating agent in step of making a compound ofFormula 17 is diethylazodicaroxylate (DEAD) with triphenylphosphine ordiisopropyl azodicarboxylate (DIAD) with triphenylphosphine; and thereducing agent in the step of making a compound of Formula 18 is sodiumborohydride. 38-43. (canceled)
 44. The method of claim 37, wherein thebase in the making of a compound of Formula 16 is potassium carbonate.45-49. (canceled)